Diamide compounds and compositions containing the same

ABSTRACT

The present invention relates to compounds represented by the following general formula ( 1 ):  
                 
 
     wherein A is a phenyl, naphthyl, dihydronaphthyl, indenyl, pyridyl, indolyl, isoindolyl, quinolyl or isoquinolyl group which may be substituted; X is a lower alkylene group which may be substituted, or the like; Y is a single bond or an alkylene group; Z is a group of —CH═CH—, —C≡C—, —(CH═CH) 2 -, —C≡C—CH═CH— or —CH═CH—C≡C—, or the like; and R is a hydrogen atom, a lower alkyl group or the like, and medicines comprising such a compound. These compounds have an excellent inhibitory effect on the production of an IgE antibody and are hence useful as antiallergic agents and the like.

TECHNICAL FIELD

[0001] The present invention relates to novel diamide compounds andmedicines useful in preventing and treating allergic immunologicaldiseases, comprising such a compound as an active ingredient.

BACKGROUND ART

[0002] IgE, which is a kind of immunoglobulin (Ig), is anallergen-specific molecule produced by an IgE producing celldifferentiated from a B cell. This process is triggered by the contactof an immunocyte with an allergen in vivo.

[0003] IgE is produced in a target organ for an allergy and binds to areceptor on the surface of a mast cell, which is a central effector cellin an allergic reaction, or a basophil (sensitized state). After thesensitization, allergic chemical mediators such as histamine,leukotrienes, prostaglandins and PAF, and injuring enzymes such astryptase are released from the mast cell stimulated by the reaction ofthe specific IgE and the allergen which invades in the living body, sothat immediate responses, such as vascular permeability acceleration,smooth muscle constriction, and vasodilation are elicited. Further,cytokines such as IL-4, which directly activate other immune systemcells, are also secreted from the stimulated mast cell. As a result,eosinophils, basophils and the like infiltrate into a tissue, and theallergic chemical mediators and tissue injuring proteins such as MBP,which are secreted by these inflammatory cells, induce a late response,so that the allergic symptom is lingered and taken seriously ill.

[0004] From this, IgE is considered a substance fundamentallyparticipating in the attack of an allergic immunological disease.

[0005] Therefore, several compounds having an inhibitory effect on theproduction of an IgE antibody have heretofore been found and reportedwith a view toward developing antiallergic agents [Pharmacology andTherapy, 1994, 22(3), 1369; Japanese Patent Application Laid-Open No.106818/1989; Japanese Patent Publication No. 17506/1995; and JapanesePatent Application Laid-Open No. 92216/1996]. However, the object hasbeen not always sufficiently achieved under the circumstances.

[0006] Accordingly, it is an object of the present invention to find acompound having a strong inhibitory effect on the production of an IgEantibody so as to provide a medicine effective for allergicimmunological diseases, comprising this compound as an activeingredient.

DISCLOSURE OF THE INVENTION

[0007] With the foregoing circumstances in view, the present inventorshave carried out an extensive investigation. As a result, it has beenfound that novel diamide compounds represented by the general formula(1), which will be described subsequently, salts thereof, or solvatesthereof have an excellent inhibitory effect on the production of an IgEantibody and are useful as prophylactic and therapeutic agents forvarious allergic immunological diseases, thus leading to completion ofthe present invention.

[0008] According to the present invention, there is thus provided acompound represented by the following general formula (1):

[0009] wherein A is a phenyl, naphthyl, dihydronaphthyl, indenyl,pyridyl, indolyl, isoindolyl, quinolyl or isoquinolyl group which may besubstituted;

[0010] X is a lower alkylene group which may be substituted; a divalentresidue of an alicyclic compound which may be substituted, an aromaticcompound which may be substituted, or a heterocyclic compound which maybe substituted; an imino group which may be substituted; or a sulfuratom or an oxygen atom;

[0011] Y is a single bond or a lower alkylene group;

[0012] Z is a group of —CH═CH—, —C≡C—, —(CH═CH)₂-, —C═C—CH═CH— or—CH═CH—C≡C—, or a divalent residue of benzene, pyridine, pyrimidine orpyrazine which may be substituted; and

[0013] R is a hydrogen atom, or a lower alkyl, cycloalkyl, aryl oraralkyl group, with the proviso that A is not a phenyl group, a4-chlorophenyl group nor a 4-methoxyphenyl group when X is an ethylenegroup, Y is a single bond, Z is —C≡C—, and R is a hydrogen atom; A isnot a 3,4-dichlorophenyl group when X is a trimethylene group, Y is asingle bond, Z is —(CH═CH)₂-, and R is a hydrogen atom; and A is not a3,4-dihydroxyphenyl group, a 3-hydroxy-4-methoxyphenyl group, a3-methoxy-4-hydroxyphenyl group nor a 3,4-dimethoxyphenyl group when Xis a tetramethylene group, Y is a single bond, Z is —CH═CH— or—(CH═CH)₂-, and R is a hydrogen atom, a salt thereof, or a solvatethereof.

[0014] According to the present invention, there is also provided amedicine comprising the above compound as an active ingredient.

[0015] According to the present invention, there is further provided amedicinal composition comprising the above compound and apharmaceutically acceptable carrier.

[0016] According to the present invention, there is still furtherprovided use of the above compound for a medicine.

[0017] According to the present invention, there is yet still furtherprovided a method of treating an allergic immunological disease, whichcomprises administering an effective amount of the above compound.

BEST MODE FOR CARRYING OUT THE INVENTION

[0018] The diamide compounds according to the present invention arerepresented by the general formula (1). As compounds similar to thesecompounds, 5-phenyl-2,4-pentadiene derivatives are described in J. Med.Chem., 1968, 11, 1073. However, these compounds are described only asantimalarial drugs, not as antiallergic agents. Japanese PatentApplication Laid-Open No. 214766/1985 also describes compounds similarto the compounds (1) according to the present invention. However, thepublication describes these compounds as 5-lipoxygenase inhibitors, butdoes not describe anything about the fact that they have an inhibitoryeffect on the production of an IgE antibody.

[0019] In the present invention, “alkyl” in alkyl groups, alkylaminogroups, dialkylamino groups and the like means linear or branched alkylgenerally having 1-12 carbon atoms, and lower alkyl groups arepreferred. The lower alkyl groups include linear or branched alkylgroups having 1-8 carbon atoms. Specific examples thereof includemethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl,tert-butyl, pentyl, hexyl, heptyl and octyl groups. Of these, thosehaving 1-6 carbon atoms, for example, methyl, ethyl, propyl, i-propyl,n-butyl, i-butyl, tert-butyl, n-pentyl and n-hexyl groups, areparticularly preferred.

[0020] “Alkoxy” in alkoxy groups, alkoxycarbonyl groups and the likemeans linear or branched alkoxy generally having 1-12 carbon atoms, andlower alkoxy groups are preferred. The lower alkoxy groups includelinear or branched alkoxy groups having 1-8 carbon atoms. Specificexamples thereof include methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, i-butoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy,heptyloxy and octyloxy groups. Of these alkoxy groups, those having 1-6carbon atoms are preferred.

[0021] Lower alkylene groups include linear or branched alkylene groupshaving 1-8 carbon atoms. Specific examples thereof include methylene,ethylene, propylene, trimethylene, tetramethylene, pentamethylene,hexamethylene, heptamethylene and octamethylene groups.

[0022] Alicyclic compounds include saturated alicyclic hydrocarbonshaving 3-8 carbon atoms, for example, cycloalkanes such as cyclopentane,cyclohexane, cycloheptane and cyclooctane.

[0023] Aromatic compounds include aromatic compounds having 6-14 carbonatoms, such as benzene and naphthalene.

[0024] Heterocyclic compounds include 5- to 7-membered heterocycliccompounds containing 1-3 nitrogen atoms, such as pyrrolidine, pyridine,piperidine, piperazine and homopiperazine.

[0025] Cycloalkyl groups include cycloalkyl groups having 3-8 carbonatoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl groups.

[0026] Aryl groups include aromatic groups having 6-14 carbon atoms,such as phenyl and naphthyl groups. Aralkyl groups include C₆₋₁₄-aryl-C₁₋₈-alkyl groups such as benzyl, phenylethyl and naphthylmethyl groups.

[0027] Alkylthio groups include alkylthio groups having 1-8 carbonatoms.

[0028] Halogen atoms include fluorine, chlorine, bromine and iodineatoms.

[0029] In the formula (1), A is a phenyl, naphthyl, dihydronaphthyl,indenyl, pyridyl, indolyl, isoindolyl, quinolyl or isoquinolyl group.These groups may have 1-3 substituents. Here, examples of thesubstituents on these groups include a hydroxyl group, halogen atoms,lower alkyl groups which may be substituted by 1-3 halogen atoms, loweralkoxy groups, an amino group which may be substituted by one or twolower alkyl groups, and alkylthio groups. As A, a phenyl groupsubstituted by 1-3 substituents selected from among lower alkyl groupsand lower alkoxy groups is particularly preferred.

[0030] The lower alkylene group represented by X is preferably a linearor branched alkylene group having 1-8 carbon atoms. A linear alkylenegroup having 5-8 carbon atoms is more preferred, with a hexamethylenegroup being particularly preferred. It is also preferred that X be anethylene group. These groups may have a substituent such as a halogenatom, or a hydroxyl, lower alkoxy, carboxyl or lower alkoxycarbonylgroup. Of these, a lower alkylene group which may be substituted by acarboxyl or lower alkoxycarbonyl group is particularly preferred.

[0031] The divalent residue of the alicyclic compound, which isrepresented by X, is preferably a divalent residue of a cycloalkanehaving 5-8 carbon atoms. Examples of the divalent residue of thearomatic compound, which is represented by X, include phenylene andnaphthylene groups, with a phenylene group being particularly preferred.Here, the phenylene group may be any of 1,2-phenylene, 1,3-phenylene and1,4-phenylene groups, with a 1,2-phenylene or 1,4-phenylene group beingparticularly preferred. Preferable examples of the divalent residue ofthe heterocyclic compound, which is represented by X, include divalentresidues of pyridine, pyrrolidine, piperidine, piperazine,homopiperazine and the like. The divalent residue of the alicycliccompound, aromatic compound or heterocyclic compound, or the iminogroup, which is represented by X, may be substituted by a halogen atom,a hydroxyl group, a lower alkyl group which may be substituted by aprimary, secondary or tertiary amino group, a lower alkoxy group, acarboxyl group, a lower alkoxy-carbonyl group, an amino group, analkylamino group, a dialkylamino group, a nitro group, a cyano group, anaralkyl group, or the like. Here, examples of the primary, secondary ortertiary amino group include amino, lower alkylamino and di-loweralkylamino groups.

[0032] X is preferably the divalent residue of the alicyclic compoundwhich may be substituted, the divalent residue of the aromatic compoundwhich may be substituted, or the divalent residue of the heterocycliccompound which may be substituted.

[0033] The lower alkylene group represented by Y is preferably a linearor branched alkylene group having 1-8 carbon atoms.

[0034] Examples of groups which may be substituted on the divalentresidue of benzene, pyridine, pyrimidine or pyrazine represented by Zinclude halogen atoms, and lower alkyl, lower alkoxy, amino and nitrogroups.

[0035] R is preferably a hydrogen atom, or a lower alkyl, cycloalkyl,phenyl or aralkyl group, with a hydrogen atom, a lower alkyl group, acycloalkyl group having 5-8 carbon atoms, a phenyl group, a benzyl groupor a phenylethyl group being particularly preferred.

[0036] In the formula (1), A is not a phenyl group, a 4-chlorophenylgroup nor a 4-methoxyphenyl group when X is an ethylene group, Y is asingle bond, Z is —C≡C—, and R is a hydrogen atom. Also, A is not a3,4-dichlorophenyl group when X is a trimethylene group, Y is a singlebond, Z is —(CH═CH)₂-, and R is a hydrogen atoms. Further, A is not a3,4-dihydroxyphenyl group, a 3-hydroxy-4-methoxyphenyl group, a3-methoxy-4-hydroxyphenyl group nor a 3,4-di-methoxyphenyl group when Xis a tetramethylene group, Y is a single bond, Z is —CH═CH— or—(CH═CH)₂-, and R is a hydrogen atom.

[0037] Among the above-described compounds, compounds obtained inExamples 3, 5, 13, 15, 22, 26, 29, 48, 49, 51, 55 and 57, which will bedescribed subsequently, are particularly preferred in the presentinvention.

[0038] No particular limitation is imposed on the salts of the diamidecompounds (1) according to the present invention so far as they arepharmaceutically acceptable salts. In the case where the diamidecompounds (1) are basic compounds, however, examples of the saltsinclude mineral acid salts such as hydrochlorides and sulfates; organicacid salts such as methanesulfonates, acetates, oxalates and citrates.In the case where the diamide compounds (1) are acidic compounds on theother hand, examples of the salts include alkali metal salts such assodium salts and potassium salts; alkaline earth metal salts such ascalcium salts and magnesium salts; and organic basic salts such aspyridine salts, picoline salts and triethylamine salts.

[0039] The diamide compounds (1) may be present in the form of solvatessuch as hydrates.

[0040] The diamide compounds (1) can be prepared according to, forexample, the following reaction formula:

[0041] wherein A, X, Y, Z and R have the same meanings as defined above.

[0042] More specifically, the compounds (1) according to the presentinvention are obtained by the N-acylating reaction of a carboxylic acid(2) with a diamine (3).

[0043] The N-acylating reaction may be conducted by using anyN-acylating reaction known per se in the art. It is particularlypreferable to apply, for example, (a) a method in which the carboxylicacid (2) and the diamine (3) are reacted in the presence of acondensation reagent, preferably, a base and a condensation reagent in asolvent, or (b) a method in which a reactive derivative of thecarboxylic acid (2) and the diamine (3) are reacted in a solvent.

[0044] Examples of the solvents used in these reactions may includedimethylformamide, tetrahydrofuran, dioxane, acetonitrile, methylenechloride and dichloroethane. As the base, may be used an organic basesuch as pyridine, triethylamine or diisopropylethylamine, or aninorganic base such as sodium carbonate or sodium hydrogencarbonate.Examples of usable condensation agents include1,3-dicyclohexylcarbodiimide,1-cyclohexyl-3-morpholinoethyl-carbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1,1′-carbonyldiimidazole,diethyl phosphorocyanidate, diphenylphosphoryl azide,bis(2-oxo-3-oxazolidinyl)-phosphinic chloride and2-chloro-1-methylpyridinium iodide. Examples of usable derivatives ofthe carboxylic acid Include acid halides such as acid chlorides, acidazides, symmetric acid anhydrides, mixed anhydrides with pivalic acid orthe like, and active esters such as cyanomethyl esters and p-nitrophenylesters.

[0045] In each of the method (a) and the method (b), the N-acylatingreaction is completed by reacting the carboxylic acid (2) with thediamine (3) at a reaction temperature of 0° C. to 100° C. for 30 minutesto 30 hours. The isolation and purification of the compound (1) from thereaction mixture may be conducted by using any methods known per se inthe art, for example, filtration, extraction, washing, drying,concentration, recrystallization and various kinds of chromatography.

[0046] The compound (1) thus obtained may be converted into anacid-addition salt or a basic salt in a method known per se in the art.

[0047] The compound may also be converted into a solvate with a solventfor recrystallization, or the like, in particular, a hydrate.

[0048] Since the diamide compounds (1) according to the presentinvention have an excellent inhibitory effect on the production of anIgE antibody as demonstrated in Examples, which will be describedsubsequently, they are useful as medicines for prevention and treatmentof various allergic immunological diseases, in which IgE participates,for example, asthma, atopic dermatitis, allergic rhinitis, inflammatorylarge bowel diseases, contact dermatitis and allergic ophthalmopathy.

[0049] The diamide compounds (1) or the salts thereof according to thepresent invention can be formulated into various oral and parenteralpreparations in the form of a solid, semisolid or liquid by adding apharmaceutically acceptable, inorganic or organic carrier in accordancewith a method known per se in the art.

[0050] Examples of the oral preparations include tablets, pills,granules, soft and hard capsules, powders, grains, triturations,emulsions, syrups, pellets and elixirs. Examples of the parenteralpreparations include injections, drops, infusions, ointments, lotions,tonics, sprays, suspensions, oils, emulsions, suppositories and eyedrops. The active ingredients according to the present invention may beformulated into various preparations in accordance with a method knownper se in the art. In these preparations, may be suitably usedsurfactants, excipients, colorants, smell corrigents, preservatives,stabilizers, buffers, suspension stabilizers, isotonic agents and thelike, as needed.

[0051] The dose of the diamide compound (1) or the salt thereof variesaccording to the kind of the compound, the kind of a disease to betreated or prevented, an administration method, the condition, age, sex,weight of a patient to be administered, treatment time, and the like.However, the compound may be administered in a dose of 0.01-1,000 mg/kgof weight/day. The compound may be administered at once or in severalportions, for example, 2 to 6 portions a day.

EXAMPLES

[0052] The present invention will hereinafter be described in moredetail by the following Examples. However, the present invention is notlimited to these examples.

Example 1

[0053] Preparation ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]ethylenediamine:

[0054] A solution of 196 mg (0.74 mmol) of ethylenediamine in anhydrousdimethylformamide (0.9 ml) was cooled in an ice bath, and to thesolution were added 29.4 mg (0.34 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid, 0.12 ml (0.86mmol) of triethylamine and 0.11 ml (0.74 mmol) of diethylphosphorocyanidate. The ice bath was removed, and the mixture wasstirred for 1 hour at room temperature. Added to the reaction mixturewas a 5% aqueous solution (4 ml) of sodium hydrogencarbonate to conductextraction with chloroform. An organic layer was dried over anhydroussodium sulfate and then concentrated under reduced pressure. Theresultant crude oil (274 mg) was purified by column chromatography onalumina and column chromatography on silica gel, thereby obtaining 147mg (yield: 76%) of the title compound as a colorless crystalline powder.

[0055] Melting point: 213-214° C.

[0056]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0057] 3.29 (br s,4H), 3.72(s,6H), 3.82(2,12H),

[0058] 6.11(d,J=15.0 Hz,2H), 6.79(d,J=15.5 Hz,2H), 6.81 (s,4H),

[0059] 6.89(dd,J=15.5,9.9 Hz,2H), 7.17(dd,J=15.0,9.9 Hz,2H),

[0060] 7.66(br s,2H).

Example 2

[0061] Preparation ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-N,N′-dimethylethylenediamine:

[0062] In accordance with the same process as in Example 1, 147 mg(yield: 76%) of the title compound was obtained as a colorless amorphouspowder from 198 mg (0.75 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 29 mg (0.33mmol) of N,N′-dimethylethylenediamine. ¹H-NMR (DMSO-d₆, 120° C.)(mixture of amide rotamers) δ:

[0063] 3.01(s,6H), 3.58(s,4H), 3.71(s,6H), 3.80(s,12H),

[0064] 6.50-6.85(m,4H), 6.77(s,4H),

[0065] 6.92(dd, J=15.3, 10.4 Hz, 2H), 7.20(dd,J=14.6, 10.4 Hz,2H).

Example 3

[0066] Preparation ofN,N′-bis(5-[3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-N,N′-dibenzylethylenediamine:

[0067] In accordance with the same process as in Example 1, 286 mg(yield: 94%) of the title compound was obtained as a colorless amorphouspowder from 241 mg (0.91 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 100 mg (0.42mmol) of N,N′-dibenzylethylenediamine. ¹H-NMR (DMSO-d₆, 120° C.) δ:

[0068] 3.51(s,4H), 3.71(s,6H), 3.80(s,12H), 4.61(s,4H),

[0069] 6.59(d,J=14.4 Hz,2H), 6.78(s,4H), 6.82(d,J=15.4 Hz,2H),

[0070] 6.91(dd,J=15.4,9.5 Hz,2H), 7.18-7.36(m,12H).

Example

[0071] Preparation of N,N′-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-N,N′-diphenyl-1,3-diaminopropane:

[0072] A solution of 174 mg (0.66 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid in anhydrousdimethylformamide-methylene chloride (0.1 ml-5 ml) was cooled in an icebath, and to the solution was added 0.080 ml (0.92 mmol) of oxalylchloride with stirring. The ice bath was removed, and the mixture wasstirred for 30 minutes at room temperature. The reaction mixture wasconcentrated under reduced pressure to obtain crude crystals of5-(3,4,5-trimethoxyphenyl)penta-(2E, 4E)-dienoyl chloride.

[0073] A solution of 5-(3,4,5-trimethoxyphenyl)penta-(2E, 4E)-dienoylchloride in methylene chloride (3 ml) was added dropwise to a solutionof 68 mg (0.30 mmol) of N,N′-diphenyl-1,3-diaminopropane in pyridine (3ml) with stirring in an ice bath. After completion of the addition, themixture was stirred for an additional 1 hour, and a 5% aqueous solution(5 ml) of sodium hydrogencarbonate was added to the reaction mixture toconduct extraction with chloroform. An organic layer was dried overanhydrous sodium sulfate and then concentrated under reduced pressure.The resultant crude oil (278 mg) was purified by column chromatographyon silica gel, thereby obtaining 126 mg (yield: 59%) of the titlecompound as a colorless amorphous powder.

[0074]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0075] 1.73 (br quint,J=7.3 Hz,2H), 3.70(s,6H),

[0076] 3.75(br t,J=7.3 Hz,4H), 3.77(s,12H),

[0077] 5.87(d,J=14.7 Hz,2H), 6.68-6.83(m,4H), 6.76(s,4H),

[0078] 7.15-7.28(m,6H), 7.31-7.47(m,6H).

Example 5

[0079] Preparation ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-N,N′-dimethyl-1,6-diaminohexane:

[0080] In accordance with the same process as in Example 1, 194 mg(yield: 94%) of the title compound was obtained as a colorless amorphouspowder from 170 mg (0.64 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 47 mg (0.32mmol) of N,N′-dimethyl-1,6-diaminohexane. ¹H-NMR (DMSO-d₆, 120° C.) 67 :

[0081]1.27-1.39(m,4H), 1.55(br tt,J=7.2,7.2 Hz,4H),

[0082] 2.96(s,6H), 3.37(br t,J=7.2 Hz,4H), 3.72(s,6H),

[0083] 3.81(s,12H), 6.57(d,J=14.6 Hz,2H),

[0084] 6.79(d,J=15.5 Hz,2H), 6.80(s,4H),

[0085] 6.96(dd,J=15.5,10.8 Hz,2H), 7.19(dd,J=14.6,10.8 Hz,2H).

Example 6

[0086] Preparation ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-N,N′-dibenzyl-1,6-diaminohexane:

[0087] In accordance with the same process as in Example 1, 165 mg(yield: 77%) of the title compound was obtained as a colorless amorphouspowder from 147 mg (0.56 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 100 mg (0.27mmol) of N,N′-dibenzyl-1,6-diaminohexane dihydrochloride.

[0088]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0089] 1.18-1.31(m,4H), 1.41-1.56(m,4H),

[0090] 3.33(br t,J=7.4 Hz,4H), 3.72(s,6H), 3.80(s,12H),

[0091] 4.61(s,4H), 6.60(d,J=14.7 Hz,2H), 6.80(s,4H),

[0092] 6.81(d,J=15.6 Hz,2H), 6.69(dd,J=15.6,10.5 Hz,2H),

[0093] 7.18-7.35(m,12H).

Example 7

[0094] Preparation ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-N,N′-dicyclohexyl-1,6-diaminohexane:

[0095] In accordance with the same process as in Example 1, 167 mg(yield: 75%) of the title compound was obtained as a pale brownamorphous powder from 154 mg ( 0.58 mmol) of5-(3,4,5-trimethoxyphenyl)penta- (2E,4E) -dienoic acid and 102 mg (0.29mmol) of N,N′-dicyclohexyl-1,6-diaminohexane dihydrochloride.

[0096]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0097]1.03-1.83(m,28H), 3.25(br t,J=7.7 Hz,4H), 3.72(s,6H),

[0098] 3.81(s,12H), 3.85-4.01(m,2H), 6.55(d,J=14.7 Hz,2H),

[0099] 6.78(d,J=15.4 Hz,2H), 6.80(s,4H),

[0100] 6.97(dd,J=15.4,10.7 Hz,2H), 7.20(d,J=14.7,10.7 Hz,2H).

Example 8

[0101] Preparation ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-N,N′-diphenyl-1,6-diaminohexane:

[0102] In accordance with the same process as in Example 4, 149 mg(yield: 59%) of the title compound was obtained as a colorless amorphouspowder from 174 mg (0.66 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 89 mg (0.33mmol) of N,N′-diphenyl-1,6-diaminohexane. ¹H-NMR (DMSO-d₆, 120° C.) δ:

[0103] 1.19-1.33(m,4H), 1.38-1.52(m,4H),

[0104] 3.70(br t,J=7.3 Hz,4H), 3.70(s,6H), 3.77(s,12H),

[0105] 5.90(d,J=14.7 Hz,2H), 6.69-6.82(m,4H), 6.76(s,4H),

[0106] 7.16-7.48(m,12H).

Example 9

[0107] Preparation ofNα,Nε-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-lysinemethyl ester:

[0108] In accordance with the same process as in Example 1, 451 mg(yield: 69%) of the title compound was obtained as a colorless amorphouspowder from 529 mg (2.0 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 233 mg (1.0mmol) of lysine methyl ester dihydrochloride.

[0109]¹H-NMR (CDC1₃) (mixture of amide rotamers) δ:

[0110] 1.32-1.53(m,2H), 1.53-1.68(m,2H), 1.68-2.00(m,2H),

[0111] 3.27-3.45(m,2H), 3.75(s,3H), 3.75-3.90(s,18H),

[0112] 4.62-4.74(m,₁1H), 6.05(br d,J=15.0 Hz,1H),

[0113] 6.14(br d,J=15.0 Hz,1H), 6.25-6.44(m,1H), 6.61(s,2H),

[0114] 6.33(s,2H), 6.68-6.87(m,5H), 7.00-7.47(m,2H).

Example 10

[0115] Preparation ofNα,Nε-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-lysine:

[0116] Added to a solution of 265 mg (0.40 mmol) ofNα,Nε-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-lysine methylester synthesized by the process of Example 9 inmethanol-tetrahydrofuran (1 ml-1 ml) was 1.0 ml (5.0 mmol) of a 5Naqueous solution of potassium hydroxide, and the mixture was stirred for3 hours at room temperature. A saturated saline solution (3 ml) andconcentrated hydrochloric acid (0.5 ml) were added to the reactionmixture to conduct extraction with chloroform. An organic layer wasdried over anhydrous sodium sulfate and then concentrated under reducedpressure. The resultant crude oil (234 mg) was purified by columnchromatography on silica gel to obtain 203 mg (yield: 80%) of the titlecompound as a colorless amorphous powder.

[0117]¹H-NMR (DMSO-d₆) δ:

[0118] (no OH proton of the carboxyl group was observed):

[0119] 1.22-1.53(m,4H), 1.53-1.87(m,2H), 3.03-3.20(m,2H),

[0120] 3.67(s,6H), 3.79(s,12H), 4.10-4.28(m,1H),

[0121] 6.13(br d,J=14.8 Hz,1H), 6.32(br d,J=14.8 Hz,1H),

[0122] 6.78(br d,J=15.2 Hz,1H), 6.79(br d,J=15.2 Hz,1H),

[0123] 6.82(br s,2H), 6.83(br s, 2H),

[0124] 6.99(br dd,J=15.2,11.0 Hz,2H),

[0125] 7.17(br dd,J=14.8,11.0 Hz,2H), 7.80-7.95(m,1H),

[0126] 8.05-8.15(m,1H).

Example 11

[0127] Preparation ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-1,4-bis(aminomethyl)cyclohexane:

[0128] In accordance with the same process as in Example 1, 114 mg(yield: 18%) of the title compound was obtained as a colorless amorphouspowder from 555 mg (2.1 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 142 mg (1.0mmol) of 1,4-bis(aminomethyl)cyclohexane.

[0129]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0130]1.29-1.52(m,8H), 1.52-1.80(m,2H),

[0131] 3.13(dd,J=6.5,6.5 Hz,4H), 3.72(s,6H),

[0132] 3.82(s,12H), 6.14(d,J=15.0 Hz,2H),

[0133] 6.78(d,J=15.4 Hz,2H), 6.80(s,4H),

[0134] 6.87(dd,J=15.4,9.7 Hz,2H), 7.14(dd,J=15.0,9.7 Hz,2H),

[0135] 7.50(br t,J=6.5 Hz,2H).

Example 12

[0136] Preparation ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-N,N′-dimethyl-1,4-bis(aminomethyl)-cyclohexane:

[0137] A solution of 100 mg (0.15 mmol) ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-1,4-bis-(aminomethyl)cyclohexanesynthesized by the process of Example 11 in anhydrous tetrahydrofuran(10 ml) was cooled in an ice bath under nitrogen. To the solution wasadded 0.20 ml (0.32 mmol) of a hexane solution (1.6 M) ofn-butyllithium. The mixture was stirred for 10 minutes, and 0.20 ml (3.2mmol) of methyl iodide was added to the mixture. The ice bath wasremoved, and the mixture was stirred for 12 hours at room temperature.Added to the reaction mixture was a 15% aqueous solution (5 ml) ofammonium chloride to conduct extraction with ethyl acetate. An organiclayer was dried over anhydrous sodium sulfate and then concentratedunder reduced pressure. The resultant crude oil (113 mg) was purified bycolumn chromatography on silica gel, thereby obtaining 62 mg (yield:60%) of the title compound as a pale yellow amorphous powder.

[0138]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0139] 1.30-1.50(m,8H), 1.75-1.90(m,2H), 2.98(s,6H),

[0140] 3.30-3.40(m,4H), 3.72(s,6H), 3.82(s,12H),

[0141] 6.55-6.85(m,4H), 6.81(s,4H),

[0142] 6.97(dd,J=15.4,10.6 Hz,2H), 7.20(dd,J=14.5,10.6 Hz,2H).

Example 13

[0143] Preparation ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-1,4-diaminocyclohexane:

[0144] In accordance with the same process as in Example 1, 107 mg(yield: 18%) of the title compound was obtained as a colorless amorphouspowder from 495 mg (2.2 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 114 mg (1.0mmol) of 1,4-diaminocyclohexane.

[0145]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0146]1.02-1.41(m,4H), 1.79-1.96(m,4H), 3.54-3.80(m,2H),

[0147] 3.72(s,6H), 3.82(s,12H), 6.11(d,J=14.9 Hz,2H),

[0148] 6.78(d,J=15.6 Hz,2H), 6.81(s,4H),

[0149] 6.87(dd,J=15.6,9.5 Hz,2H), 7.15(dd,J=14.9,9.5 Hz,2H),

[0150] 7.41(br d,J=6.8 Hz,2H).

Example 14

[0151] Preparation ofcis-N,N′-bis[5-(3,4,5-trimethoxy-phenyl)penta-(2E,4E)-dienoyl]-1,2-diaminocyclohexane:

[0152] In accordance with the same process as in Example 1, 174 mg(yield: 87%) of the title compound was obtained as a colorless amorphouspowder from 175 mg (0.66 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 40 mg (0.33mmol) of cis-1,2-diaminocyclohexane.

[0153]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0154] 1.33-1.52(m,2H), 1.54-1.81(m,6H), 3.76(s,6H),

[0155] 3.84(s,12H), 4.03-4.16(m,2H), 6.24(d,J=15.0 Hz,2H),

[0156] 6.77-6.96(m,4H), 6.83(s,4H), 7.19(dd,J=15.0,8.7 Hz,2H),

[0157] 7.29(br d,J=6.6 Hz,2H).

Example 15

[0158] Preparation oftrans-N,N′-bis[5-(3,4,5-trimethoxy-phenyl)penta-(2E,4E)-dienoyl]-1,2-diaminocyclohexane:

[0159] In accordance with the same process as in Example 1, 572 mg(yield: 94%) of the title compound was obtained as a colorless amorphouspowder from 495 mg (2.2 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 114 mg (1.0mmol) of trans-1,2-diaminocyclohexane. The thus-obtained amorphouspowder was recrystallized from methanol-ether-chloroform, therebyobtaining colorless needles. Melting point: 254-257° C. ¹H-NMR (DMSO-d₆,120° C.) δ:

[0160]1.22-1.40(m,4H), 1.64-1.74(m,2H), 1.89-2.02(m,2H),

[0161] 3.62-3.71(m,2H), 3.72(s,6H), 3.80(s,12H),

[0162] 6.06(d,J=15.1 Hz,2H), 6.75(d,J=15.5 Hz,2H),

[0163] 6.76(s,4H), 6.84(dd,J=15.5,9.8 Hz,2H),

[0164] 7.13(dd,J=15.1,9.8 Hz,2H), 7.30-7.40(m,2H).

Example 16

[0165] Preparation of(1S,2S)-N,N′-bis[5-(3,4,5-trimethoxy-phenyl)penta-(2E,4E)-dienoyl]-1,2-diaminocyclohexane:

[0166] In accordance with the same process as in Example 1, 134 mg(yield: 65%) of the title compound was obtained as a colorless amorphouspowder from 177 mg (0.67 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 39 mg (0.34mmol) of (1S,2S)-1,2-diaminocyclohexane. The thus-obtained amorphouspowder was recrystallized from ethanol-ether, thereby obtainingcolorless needles. Melting point: 234-235° C. Specific rotation: [α]²³_(D) =+240° (c 0.50, CHCl₃).

Example 17

[0167] Preparation of(1R,2R)-N,N′-bis[5-(3,4,5-trimethoxy-phenyl)penta-(2E,4E)-dienoyl]-1,2-diaminocyclohexane:

[0168] In accordance with the same process as in Example 1, 194 mg(yield: 97%) of the title compound was obtained as a colorless amorphouspowder from 175 mg (0.66 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 38 mg (0.33mmol) of (lR,2R)-1,2-diaminocyclohexane. The thus-obtained amorphouspowder was recrystallized from ethanol-ether, thereby obtainingcolorless needles. Melting point: 234-236° C. Specific rotation: [α]²³_(D) =−240° (c 0.50, CHCl₃).

Example 18

[0169] Preparation ofN,N-bis[N-[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-3-aminopropyl]methylamine:

[0170] In accordance with the same process as in Example 1, 341 mg(yield: 96%) of the title compound was obtained as a colorless amorphouspowder from 295 mg (1.1 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 81 mg (0.56mmol) of N,N-bis(3-aminopropyl)methylamine. ¹H-NMR (DMSO-d6, 120° C.)[mixture (7:1) of amide rotamers] δ:

[0171] 1.61(tt,J=7.0,7.0 Hz,0.5H), 1.62(tt,J=7.0,7.0 Hz,3.5H),

[0172] 2.16(s,0.4H), 2.17(s,2.6H), 2.36(t,J=7.0 Hz,0.5H),

[0173] 2.37(t,J=7.0 Hz,3.5H), 3.19(dt,J=7.0,7.0Hz,0.5H),

[0174] 3.21(dt,J=7.0,7.0 Hz,3.5H), 3.72(s,5.2H), 3.72(s,0.8H),

[0175] 3.81(s,10.5H), 3.82(s,1.5H), 6.11(d,J=15.0 Hz,0.2H),

[0176] 6.12(d,J=15.0 Hz,1.8H), 6.77(d,J=15.5 Hz,2H),

[0177] 6.79(s,3.5H), 6.80(s,0.5H), 6.87(dd,J=15.5,100. Hz,2H),

[0178] 7.14(dd,J=15.0,10.0 Hz,0.2H),

[0179] 7.15(dd,J=15.0,10.0 Hz,1.8H), 7.56(br t,J=7.0 Hz,2H).

Example 19

[0180] Preparation of1,4-bis[N-[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-3-aminopropyl]piperazine:

[0181] In accordance with the same process as in Example 1, 424 mg(yield: 49%) of the title compound was obtained as a colorless amorphouspowder from 660 mg (2.5 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 251 mg (1.3mmol) of 1,4-bis(3-aminopropyl)piperazine. ¹H-NMR (DMSO-d₆, 120° C.) δ:

[0182]1.62(tt,J=6.9,6.9 Hz,4H), 2.34(t,J=6.9 Hz,4H),

[0183] b 2.41(s,8H), 3.19(dt,J=6.9,6.9 Hz,4H), 3.72(s,6H),

[0184] 3.82(s,12H), 6.09(d,J=15.0 Hz,2H), 6.78(d,J=15.5 Hz,2H),

[0185] 6.80(s,4H), 6.87(dd,J=15.5,9.6 Hz,2H),

[0186] 7.14(dd,J=15.0,9.6 Hz,2H), 7.54(br t,J=6.9 Hz,2H).

Example 20

[0187] Preparation of1,4-bis[N-ethyl-N-[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-3-aminopropyl]-piperazine:

[0188] In accordance with the same process as in Example 1, 72 mg(yield: 36%) of the title compound was obtained as a pale yellowamorphous powder from 160 mg (0.61 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 69 mg (0.27mmol) of 1,4-bis(N-ethyl-3-aminopropyl)piperazine.

[0189]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0190] 1.13(t,J=7.1 Hz,6H), 1.69(tt,J=6.9,6.9 Hz,4H),

[0191] 2.32(t,J=6.9 Hz,4H), 2.43(s,8H), 3.34-3.46(m,8H),

[0192] 3.74(s,6H), 3.83(s,12H), 6.60(d,J=14.6 Hz,2H),

[0193] 6.82(s,4H), 6.82(d,J=15.5 Hz,2H),

[0194] 6.98(dd,J=15.5,10.6 Hz,2H), 7.22(dd,J=14.6,10.6 Hz,2H).

Example 21

[0195] Preparation of1,4-bis[N-benzyl-N-[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-3-aminopropyl]-piperazine:

[0196] In accordance with the same process as in Example 4, crudecrystals were obtained from 136 mg (0.51 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 97 mg (0.26mmol) of 1,4-bis(N-benzyl-3-aminopropyl)piperazine. The crude crystalswere recrystallized from chloroform-hexane, thereby obtaining 121 mg(yield: 54%) of a pale yellow crystalline poweder.

[0197] Melting point: 191-193° C.

[0198]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0199] 1.68(tt,J=7.0,7.0 Hz,4H), 2.28(t,J=7.0 Hz,4H),

[0200] 2.37(s,8H), 3.41(br t,J=7.0 Hz,4H), 3.75(s,6H),

[0201] 3.84(s,12H), 4.66(s,4H), 6.67(d,J=14.7 Hz,2H),

[0202] 6.83(s,4H), 6.86(d,J=15.6 Hz,2H),

[0203] 6.98(dd,J=15.6,10.3 Hz,2H), 7.22-7.38(m,12H).

Example 22

[0204] Preparation ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-1,4-bis(aminomethyl)benzene:

[0205] In accordance with the same process as in Example 4, crudecrystals were obtained from 318 mg (1.2 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 68 mg (0.50mmol) of 1,4-bis(aminomethyl)benzene. The thus-obtained crude crystalswere recrystallized from methanol-chloroform-hexane, thereby obtaining230 mg (yield: 73%) of the title compound as colorless fine needles.Melting point: 228-230° C. ¹H-NMR (DMSO-d₆, 120° C.) δ:

[0206] 3.72(s,6H), 3.82(s,12H), 4.35(d,J=5.9 Hz,4H),

[0207] 6.17(d,J=15.0 Hz,2H), 6.79(d,J=15.5 Hz,2H),

[0208] 6.81(s,4H), 6.89(dd,J=15.5,9.5 Hz,2H),

[0209] 7.20(dd,J=15.0,9.5 Hz,2H), 7.23(s,4H),

[0210] 8.03(br t,J=5.9 Hz,2H).

Example 23

[0211] Preparation ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-N,N′-dimethyl-1,4-bis(aminomethyl)-benzene:

[0212] In accordance with the same process as in Example 12, 117 mg(yield: 62%) of the title compound was obtained as a colorless amorphouspowder from 180 mg (0.29 mmol) ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-1,4-bis(aminomethyl)benzenesynthesized by the process of Example 22 and 0.45 ml (7.2 mmol) ofmethyl iodide. The thus-obtained amorphous powder was recrystallizedfrom chloroform-hexane to obtain a colorless crystalline powder. Meltingpoint: 223-226° C. ¹H-NMR (DMSO-d₆, 120° C.) δ:

[0213] 2.96(s,6H), 3.72(s,6H), 3.81(s,12H), 4.61(s,4H),

[0214] 6.65(d,J=14.7 Hz,2H), 6.80(s,4H), 6.83(d,J=15.1 Hz,2H),

[0215] 6.97(dd,J=15.1,10.5 Hz,2H), 7.22(s,4H),

[0216] 7.27(dd,J=14.7,10.5 Hz,2H).

Example 24

[0217] Preparation ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-1,3-bis(aminomethyl)benzene:

[0218] In accordance with the same process as in Example 1, crudecrystals were obtained from 180 mg (0.68 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 0.045 ml (0.34mmol) of 1,3-bis(aminomethyl)benzene. The thus-obtained crude crystalswere recrystallized from methanol-chloroform-hexane, thereby obtaining127 mg (yield: 59%) of the title compound as colorless flakes.

[0219] Melting point: 194-195° C.

[0220]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0221] 3.72(s,6H), 3.81(s,12H), 4.36(d,J=5.9 Hz,4H),

[0222] 6.18(d,J=15.2 Hz,2H), 6.79(d,J=15.5 Hz,2H),

[0223] 6.81(s,4H), 6.89(dd,J=15.5,9.8 Hz,2H), 7.13-7.28(m,4H),

[0224] 7.20(dd,J=15.2,9.8 Hz,2H), 8.06(br t,J=5.9 Hz,2H).

Example 25

[0225] Preparation of2,6-bis[N-methyl-N-[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]aminomethyl]-pyridine:

[0226] In accordance with the same process as in Example 1, 103 mg(yield: 22%) of the title compound was obtained as a pale yellowamorphous powder from 371 mg (1.4 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 115 mg (0.70mmol) of 2,6-bis(methylaminomethyl)pyridine.

[0227]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0228] 3.05(s,6H), 3.72(s,6H), 3.81(s,12H), 4.68(s,4H),

[0229] 6.66(d,J=14.7 Hz,2H), 6.79(d,J=15.5 Hz,2H),

[0230] 6.80(s,4H), 6.96(dd,J=15.5,10.6 Hz,2H),

[0231] 7.15(d,J=7.8 Hz,2H), 7.24(dd,J=14.7,10.6 Hz,2H),

[0232] 7.73(t,J=7.8 Hz,1H).

Example 26

[0233] Preparation ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-1,2-diaminobenzene:

[0234] In accordance with the same process as in Example 4, 378 mg(yield: 97%) of the title compound was obtained as a colorlesscrystalline powder from 400 mg (1.5 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 70 mg (0.65mmol) of 1,2-diaminobenzene.

[0235] Melting point: 226-229° C.

[0236]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0237] 3.73(s,6H), 3.82(s,12H), 6.33(d,J=15.1 Hz,2H),

[0238] 6.84(s,4H), 6.89(d,J=15.5 Hz,2H),

[0239] 6.99(dd,J=15.5,9.7 Hz,2H), 7.13-7.19(m,2H),

[0240] 7.35(dd,J=15.1,9.7 Hz,2H), 7.61-7.67(m,2H),

[0241] 9.32(br s,2H).

Example 27

[0242] Preparation ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-N,N′-dimethyl-1,2-diaminobenzene:

[0243] In accordance with the same process as in Example 12, 154 mg(yield: 88%) of the title compound was obtained as a colorless amorphouspowder from 166 mg (0.28 mmol) ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-1,2-diaminobenzenesynthesized by the process of Example 26 and 0.40 ml (6.4 mmol) ofmethyl iodide. ¹H-NMR (DMSO-d₆, 120° C.) δ:

[0244] 3.14(s,6H), 3.68(s,6H), 3.74(s,12H),

[0245] 6.02(br-d,J=14.9 Hz,2H), 6.69-6.87(m,4H), 6.72(s,4H),

[0246] 7.21(dd,J=14.9,7.9 Hz,1H), 7.22(dd,J=14.9,7.9 Hz,1H),

[0247] 7.34-7.41(m,2H), 7.44-7.51(m,2H).

Example 28

[0248] Preparation ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-N,N′-dibenzyl-1,2-diaminobenzene:

[0249] In accordance with the same process as in Example 12, 147 mg(yield: 67%) of the title compound was obtained as a pale yellowamorphous powder from 168 mg (0.28 mmol) ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-1,2-diaminobenzenesynthesized by the process of Example 26 and 0.65 ml (5.5 mmol) ofbenzyl bromide.

[0250]¹H-NMR (DMSO-d₆, 120° C.) (mixture of amide rotamers) δ:

[0251] 3.64-3.78(m,18H), 3.60-5.30(br,4H),

[0252] 6.03(br d,J=14.8 Hz,2H), 6.69-6.85(m,8H),

[0253] 7.00-7.08(m,2H), 7.13-7.41(m,14H).

Example 29

[0254] Preparation ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-2,3-diaminophenol:

[0255] A solution of 286 mg (1.1 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid in anhydrousdimethylformamide-methylene chloride (0.1 ml-10 ml) was cooled in an icebath. To the solution was added 0.12 ml (1.3 mmol) of oxalyl chloridewith stirring. The ice bath was removed, and the mixture was stirred for30 minutes at room temperature. The reaction mixture was concentratedunder reduced pressure to obtain crude crystals of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl chloride.

[0256] Added to a solution of 44 mg (0.35 mmol) of 2,3-diaminophenol inanhydrous methylene chloride was 2 ml (25 mmol) of pyridine, and theresultant mixture was cooled in an ice bath. A solution of5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl chloride in methylenechloride (5 ml) was added dropwise to the mixture over about 5 minutes.After completion of the addition, the resultant mixture was stirred foran additional 1 hour, and water was then added to conduct extractionwith chloroform. An organic layer was dried over anhydrous sodiumsulfate and then concentrated under reduced pressure. The resultantcrude oil (515 mg) was purified by column chromatography on silica gel,thereby obtaining 258 mg (yield: 85%) of crude crystals ofN,N′,O-tri[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-2,3-diaminophenolas a pale brown amorphous powder.

[0257] A solution of 196 mg (0.23 mmol) ofN,N′,O-tri[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-2,3-diaminophenolsynthesized by the process described above in anhydrousmethanol-tetrahydrofuran (3 ml-3 ml) was cooled in an ice bath. To thesolution was added 19 mg (0.14 mmol) of potassium carbonate. The icebath was removed, and the mixture was stirred for 1 hour at roomtemperature. Added to the reaction mixture were 0.5 ml of 1Nhydrochloric acid and 5 ml of a saturated saline solution to conductextraction with chloroform. An organic layer was dried over anhydroussodium sulfate and then concentrated under reduced pressure. Theresultant crude oil (515 mg) was purified by column chromatography onsilica gel, thereby obtaining 126 mg (yield: 90%) of crude crystals ofthe title compound. The crude crystals thus obtained were recrystallizedfrom ethanol-ether, thereby obtaining a pale yellow crystalline powder.

[0258] Melting point: 209-210° C.

[0259]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0260] 3.72(s,3H), 3.73(s,3H), 3.81(s,6H), 3.81(s,6H),

[0261] 6.29(d,J=15.1 Hz,1H), 6.40(d,J=15.1 Hz,1H),

[0262] 6.74(dd,J=8.2,1.5 Hz,1H), 6.83(s,2H), 6.84(s,2H),

[0263] 6.86(d,J=15.8 Hz,1H), 6.90(d,J=15.8 Hz,1H),

[0264] 6.97(dd,J=15.8,10.0 Hz,1H), 6.99(dd,J=15.8,10.0 Hz,1H),

[0265] 7.07(dd,J=8.2,8.2 Hz,1H), 7.27(dd,J=8.2,1.5 Hz,1H),

[0266] 7.31(dd,J=15.1,10.0 Hz,1H) 7.36(dd,J=15.1,10.0 Hz,1H),

[0267] 9.08(br s,1H), 9.10(br s,2H).

Example 30

[0268] Preparation of methylN,N′-bis[5-(3,4,5-trimethoxy-phenyl)penta-(2E,4E)-dienoyl]-3,4-diaminobenzoate:

[0269] In accordance with the same process as in Example 4, crudecrystals were obtained from 389 mg (1.5 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 107 mg (0.65mmol) of methyl 3,4-diaminobenzoate. The crude crystals wererecrystallized from ethanol-ether, thereby obtaining 305 mg (yield: 72%)of the title compound as a pale yellow crystalline powder. Meltingpoint: at least 250° C. ¹H-NMR (DMSO-d₆, 120° C.) δ:

[0270] 3.73(s,3H), 3.73(s,3H), 3.82(s,6H), 3.83(s,6H),

[0271] 3.86(s,3H), 6.36(d,J=15.0 Hz,1H), 6.37(d,J=15.0 Hz,1H),

[0272] 6.85(s,2H), 6.86(s,2H), 6.91(d,J=15.5 Hz,2H),

[0273] 7.00(dd,J=15.5,9.5 Hz,2H), 7.38(dd,J=15.0,9.5 Hz,2H),

[0274] 7.75(dd,J=8.6,2.0 Hz,1H), 7.92(d,J=8.6 Hz,1H),

[0275] 8.24(d,J=2.0 Hz,1H), 9.48(br s,1H), 9.50(br s,1H).

Example 31

[0276] Preparation ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-3,4-diaminobenzoicacid:

[0277] In accordance with the same process as in Example 10, crudecrystals were obtained from 153 mg (0.23 mmol) of methylN,N′-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-3,4-diaminobenzoatesynthesized by the process of Example 30. The crude crystals wererecrystallized from ethanol-ether, thereby obtaining 141 mg (yield: 94%)of the title compound as a pale yellow crystalline powder. Meltingpoint: 202-205° C. ¹H-NMR (DMSO-d₆, 120° C.) (no OH proton of thecarboxyl group was observed) δ:

[0278] 3.73(s,6H), 3.82(s,6H), 3.82(s,6H),

[0279] 6.36(d,J=14.9 Hz,1H), 6.36(d,J=14.9 Hz,1H),

[0280] 6.85(s,2H), 6.86(s,2H), 6.91(d,J=15.5 Hz,2H),

[0281] 7.00(dd,J=15.5,9.5 Hz,2H), 7.38(dd,J=14.9,9.5 Hz,2H),

[0282] 7.74(dd,J=8.4,2.0 Hz,1H), 7.88(d,J=8.4 Hz,1H),

[0283] 8.21(d,J=2.0 Hz,1H), 9.47(br s,2H).

Example 32

[0284] Preparation ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-1,2-diamino-4-methoxybenzene:

[0285] In accordance with the same process as in Example 4, crudecrystals were obtained from 171 mg (0.65 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 65 mg (0.31mmol) of 1,2-diamino-4-methoxybenzene dihydrochloride. The crudecrystals were recrystallized from ethanol-ether, thereby obtaining 133mg (yield: 68%) of the title compound as a pale yellow crystallinepowder.

[0286] Melting point: 231-233° C.

[0287]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0288] 3.73(s,6H), 3.77(s,3H), 3.82(s,6H), 3.82(s,6H),

[0289] 6.30(d,J=15.0 Hz,1H), 6.31(d,J=15.0 Hz,1H),

[0290] 6.75(dd,J=8.8,2.8 Hz,1H), 6.84(s,4H),

[0291] 6.87(d,J=15.4 Hz,1H), 6.88(d,J=15.4 Hz,1H),

[0292] 6.98(dd,J=15.4,9.9 Hz,1H), 6.99(dd,J=15.4,9.9 Hz,1 H),

[0293] 7.33(dd,J=15.0,9.9 Hz,1H), 7.34(dd,J=15.0,9.9 Hz,1H),

[0294] 7.38(d,J=2.8 Hz,1H), 7.43(d,J=8.8 Hz,1H), 9.18(br s,1H),

[0295] 9.26(br s,1H).

Example 33

[0296] Preparation ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-1,2-diamino-4-nitrobenzene:

[0297] In accordance with the same process as in Example 4, crudecrystals were obtained from 623 mg (2.2 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 153 mg (1.0mmol) of 1,2-diamino-4-nitrobenzene dihydrochloride. The crude crystalswere recrystallized from ethyl acetate-chloroform-hexane, therebyobtaining 492 mg (yield: 76%) of the title compound as a pale yellowcrystalline powder. Melting point: 237-239° C. ¹H-NMR (DMSO-d₆, 120° C.)δ:

[0298] 3.73(s,6H), 3.83(s,6H), 3.83(s,6H),

[0299] 6.38(d,J=14.9 Hz,1H), 6.41(d,J=14.9 Hz,1H),

[0300] 6.86(s,2H), 6.87(s,2H), 6.94(d,J=15.5 Hz,2H),

[0301] 7.02(dd,J=15.5,8.4 Hz,2H), 7.41(br dd,J=14.9,8.4 Hz,2H),

[0302] 8.00(dd,J=9.0,2.4 Hz,1H), 8.09(d,J=9.0 Hz,1H),

[0303] 8.60(d,J=2.4 Hz,1H), 9.60(br s,1H), 9.64(br s,1H).

Example 34

[0304] Preparation ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-1,4-diaminobenzene:

[0305] In accordance with the same process as in Example 4, crudecrystals were obtained from 350 mg (1.3 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 121 mg (0.67mmol) of 1,4-diaminobenzene dihydrochloride. The crude crystals wererecrystallized from dimethylformamide-ether, thereby obtaining 135 mg(yield: 34%) of the title compound as a yellow crystalline powder.

[0306] Melting point: 270° C.

[0307]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0308] 3.73(s,6H), 3.83(s,12H), 6.31(d,J=15.1 Hz,2H),

[0309] 6.85(s,4H), 6.87(br d,J=15.5 Hz,2H),

[0310] 6.95(dd,J=15.5,9.2 Hz,2H),

[0311] 7.32(ddd,J=15.1,9.2,0.7 Hz,2H), 7.58(s,4H),

[0312] 9.58(br s,2H).

Example 35

[0313] Preparation of methylN,N′-bis[5-(3,4,5-trimethoxy-phenyl)penta-(2E,4E)-dienoyl]-3,5-diaminobenzoate:

[0314] In accordance with the same process as in Example 4, crudecrystals were obtained from 340 mg (1.3 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 105 mg (0.64mmol) of methyl 3,5-diaminobenzoate. The crude crystals wererecrystallized from chloroform-ether, thereby obtaining 301 mg (yield:72%) of the title compound as a pale yellow crystalline powder. Meltingpoint: 158-162° C. ¹H-NMR (DMSO-d₆, 120° C.) δ:

[0315]3.74(s,6H), 3.84(s,12H), 3.87(s,3H),

[0316] 6.34(d,J=14.9 Hz,2H), 6.86(s,4H),

[0317] 6.90(br d,J=15.4 Hz,2H), 6.98(dd,J=15.4,9.0 Hz,2H),

[0318] 7.36(ddd,J=14.9,9.0,1.0 Hz,2H), 7.99(d,J=2.1Hz,2H),

[0319] 8.33(t,J=2.1 Hz,1H), 9.91(br s,2H).

Example 36

[0320] Preparation ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-3,5-diaminobenzoicacid:

[0321] In accordance with the same process as in Example 10, crudecrystals were obtained from 161 mg (0.24 mmol) of methylN,N′-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-3,5-diaminobenzoatesynthesized by the process of Example 35. The crude crystals wererecrystallized from ethanol-ether, thereby obtaining 156 mg (yield: 99%)of the title compound as a pale yellow crystalline powder. Meltingpoint: 250° C. ¹H-NMR (DMSO-d₆, 120° C.) (no OH proton of the carboxylgroup was observed) δ:

[0322] 3.74(s,6H), 3.84(s,12H), 6.36(d,J=14.9 Hz,2H),

[0323] 6.86(s,4H), 6.89(br d,J=15.4 Hz,2H),

[0324] 6.98(dd,J=15.4,9.2 Hz,2H),

[0325] 7.36(ddd,J=14.9,9.2,1.0 Hz,2H), 7.97(d,J=2.0 Hz,2H),

[0326] 8.30(t,J=2.0 Hz,1H), 9.90(br s,2H).

Example 37

[0327] Preparation ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoyl]-1,3-diamino-5-(N,N-dimethyl-aminomethyl)benzene:

[0328] In accordance with the same process as in Example 4, 128 mg(yield: 63%) of the title compound was obtained as a pale yellowamorphous powder from 152 mg (0.58 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 51 mg (0.31mmol) of 1,3-diamino-5-(N,N-dimethylaminomethyl)-benzene.

[0329]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0330] 2.24(s,6H), 3.41(s,2H), 3.73(s,6H), 3.83(s,12H),

[0331] 6.34(d,J=14.9 Hz,2H), 6.86(s,4H),

[0332] 6.87(br d,J=15.4 Hz,2H), 6.96(dd,J=15.4,9.3 Hz,2H),

[0333] 7.32(ddd,J=14.9,9.3,1.0 Hz,2H), 7.33(d,J=2.0 Hz,2H),

[0334] 7.95(t,J=2.0 Hz,1H), 9.65(br s,2H).

Example 38

[0335] Preparation of2,3-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoylamino]pyridine:

[0336] In accordance with the same process as in Example 4, 255 mg(yield: 87%) of the title compound was obtained as a yellow amorphouspowder from 302 mg (1.1 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 53 mg (0.49mmol) of 2,3-diaminopyridine. ¹H-NMR (DMSO-d₆, 120° C.) (one amide NHproton was not observed) δ:

[0337] 3.73(s,3H), 3.74(s,3H), 3.82(s,6H), 3.83(s,6H),

[0338] 6.26(d,J=15.0 Hz,1H), 6.52(d,J=15.0 Hz,1H),

[0339] 6.85(s,2H), 6.86(s,2H), 6.91-7.06(m,4H),

[0340] 7.26(dd,J=8.1,4.6 Hz,1H), 7.33(dd,J=15.0,10.1 Hz,1H),

[0341] 7.46(ddd,J=15.0,8.9,1.3 Hz,1H),

[0342] 8.19(dd,J=4.6,1.6 Hz,1H), 8.31(dd,J=8.1,1.6 Hz,1H),

[0343] 9.53(br s,1H).

Example 39

[0344] Preparation of3,4-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoylamino]pyridine:

[0345] In accordance with the same process as in Example 4, 88 mg(yield: 34%) of crude crystals of the title compound were obtained from263 mg (1.0 mmol) of 5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoicacid and 47 mg (0.43 mmol) of 3,4-diaminopyridine. The crude crystalswere recrystallized from ethanol-ether, thereby obtaining a yellowcrystalline powder. Melting point: 174-176° C. ¹H-NMR (DMSO-d₆, 120° C.)δ:

[0346] 3.73(s,3H), 3.74(s,3H), 3.82(s,6H), 3.83(s,6H),

[0347] 6.36(d,J=15.0 Hz,1H), 6.37(d,J=15.0 Hz,1H), 6.85(s,2H),

[0348] 6.86(s,2H), 6.88-7.06(m,4H),

[0349] 7.39(ddd,J=15.0,7.8,1.2 Hz,1H),

[0350] 7.39(dd,J=15.0,9.3 Hz,1H), 7.94(d,J=5.5 Hz,1H),

[0351] 8.29(d,J=5.5 Hz,1H), 8.65(s,1H), 9.48(br s,2H).

Example 40

[0352] Preparation of2,6-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoylamino]pyridine:

[0353] In accordance with the same process as in Example 4, 250 mg(yield: 85%) of crude crystals of the title compound were obtained from302 mg (1.1 mmol) of 5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoicacid and 53 mg (0.49 mmol) of 2,6-diaminopyridine. The crude crystalswere recrystallized from chloroform-ether, thereby obtaining a yellowcrystalline powder. Melting point: 203-207° C. ¹H-NMR (DMSO-d₆, 120° C.)δ:

[0354] 3.74(s,6H), 3.83(s,12H), 6.51(d,J=15.1 Hz,2H),

[0355] 6.86(s,4H), 6.88-7.02(m,4H),

[0356] 7.38(ddd,J=15.1,7.6,2.5 Hz,2H), 7.67-7.82(m,3H),

[0357] 9.68(br s,2H).

Example 41

[0358] Preparation ofN,N′-bis[5-(2,6-dimethoxyphenyl)-penta-(2E,4E)-dienoyl]-1,4-bis(aminomethyl)benzene:

[0359] In accordance with the same process as in Example 1, 128 mg(yield: 68%) of the title compound was obtained as a colorless amorphouspowder from 156 mg (0.67 mmol) of5-(2,6-dimethoxyphenyl)penta-(2E,4E)-dienoic acid and 45 mg (0.33 mmol)of 1,4-bis(aminomethyl)benzene.

[0360]¹H-NMR (DMSO-d₆, 120° C.) (mixture of amide rotamers) δ:

[0361]3.83(s,12H), 4.34(d,J=5.9 Hz,4H), 6.01-6.16(m,2H),

[0362] 6.66(d,J=8.3 Hz,4H), 7.01-7.25(m,6H),

[0363] 7.19(t,J=8.3 Hz,2H), 7.23(s,4H), 7.94(br t,J=5.9 Hz,2H).

Example 42

[0364] Preparation ofN,N′-bis[5-(4-tert-butyl-2-methoxy-phenyl)penta-(2E,4E)-dienoyl]-1,4-bis(aminomethyl)benzene:

[0365] In accordance with the same process as in Example 1, crudecrystals were obtained from 152 mg (0.59 mmol) of5-(4-tert-butyl-2-methoxyphenyl)penta-(2E,4E)-dienoic acid and 40 mg(0.29 mmol) of 1,4-bis(aminomethyl)benzene. The crude crystals wererecrystallized from chloroform-hexane, thereby obtaining 117 mg (yield:65%) of the title compound as a colorless crystalline powder.

[0366] Melting point: 237-239° C.

[0367]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0368] 1.30(s,18H), 3.84(s,6H), 4.34(d,J=6.1 Hz,4H),

[0369] 6.13(br d,J=15.0 Hz,2H),

[0370] 6.89(ddd,J=15.6,10.5,0.5 Hz,2H), 6.93-7.00(m,4H),

[0371] 7.05(d,J=15.6 Hz,2H), 7.20(dd,J=15.0,10.5 Hz,2H),

[0372] 7.23(s,4H), 7.42(d,J=7.8 Hz,2H), 7.98(br t,J=6.1 Hz,2H).

Referential Example 1

[0373] Preparation of trans-1-benzyl-3,4-bis(aminomethyl)-pyrrolidine:

[0374] A solution of 291 mg (3.7 mmol) of fumaronitrile and 1.06 g (4.5mmol) of N-benzyl-N-(methoxymethyl)trimethyl-silylmethylamine inanhydrous methylene chloride (7.5 ml) was cooled in an ice bath. To thesolution was added 0.37 ml (0.37 mmol) of a 1 M solution oftrifluoroacetic acid in methylene chloride. The ice bath was removed,and the mixture was stirred for 4 hours at room temperature. Thereaction mixture was washed with a saturated solution of a sodiumhydrogencarbonate and a saturated saline solution, dried over anhydroussodium sulfate, and then concentrated under reduced pressure, therebyobtaining 789 mg of an oil containingtrans-1-benzyl-3,4-dicyanopyrrolidine⁽¹⁾. To a solution of 789 mg of theoil thus obtained in ethanol-chloroform (10:1, 22 ml) was added 54.6 mgof platinum oxide, and the resultant mixture was stirred for 3 days atroom temperature under hydrogen. The catalyst was removed by suctionfiltration through Celite, and the filtrate was concentrated underreduced pressure. To a solution of the residue in water-methanol wasadded 1.5 g (11 mmol) of potassium carbonate. The mixture was stirredand then concentrated again under reduced pressure. The resultantresidue was purified by column chromatography on alumina, therebyobtaining 403 mg (yield: 49%) of the title compound as a colorless oil.

[0375] (1) Terao, Y.; Kotaki, H.; Imai, N.; Achiwa, K., Chem.

[0376] Pharm. Bull., 1985, 33, 2762-2766.

Example 43

[0377] Preparation oftrans-1-benzyl-3,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl-aminomethyl]pyrrolidine:

[0378] In accordance with the same process as in Example 4, 88 mg(yield: 38%) of the title compound was obtained as a pale yellowamorphous powder from 191 mg (0.73 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid and 72 mg (0.33mmol) of trans-1-benzyl-3,4-bis(aminomethyl)-pyrrolidine synthesized bythe process described in Referential Example 1. ¹H-NMR (DMSO-d₆, 120°C.) δ:

[0379] 1.98-2.13(m,2H), 2.36(dd,J=9.1,5.4 Hz,2H),

[0380] 2.71(dd,J=9.1,7.1 Hz,2H),

[0381] 3.19(ddd,J=13.3,6.1,6.1 Hz,2H),

[0382] 3.25(ddd,J=13.3,6.1,6.1 Hz,2H), 3.58(s,2H), 3.72(s,6H),

[0383] 3.80(s,12H), 6.11(d,J=15.1 Hz,2H), 6.77(d,J=15.1 Hz,2H),

[0384] 6.78(s,4H), 6.86(dd,J=15.1,9.4 Hz,2H), 7.12-7.32(m,5H),

[0385] 7.15(dd,J=15.1,9.4 Hz,2H), 7.58(br t,J=6.1 Hz,2H).

Referential Example 2

[0386] Preparation oftrans-1-methyl-3,4-bis(tert-butoxycarbonylaminomethyl)pyrrolidine:

[0387] A solution of 304 mg (1.4 mmol) oftrans-1-benzyl-3,4-bis(aminomethyl)-pyrrolidine synthesized by theprocess described in Referential Example 1 in 1,4-dioxane (5 ml) wascooled in an ice bath. To the solution were added 4.2 ml (4.2 mmol) of a1N aqueous solution of sodium hydroxide and 917 mg (4.2 mmol) ofdi-tert-butyl dicarbonate, and the mixture was stirred for 1 hour. Theice bath was removed, and the mixture was stirred for 24 hours at roomtemperature. The reaction mixture was then extracted with chloroform. Anorganic layer was dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure. The resultant crude oil waspurified by column chromatography on silica gel to obtain 256 mg (yield:44%) oftrans-l-benzyl-3,4-bis(tert-butoxycarbonyl-aminomethyl)pyrrolidine as acolorless oil.

[0388] To a solution of 203 mg (0.49 mmol) oftrans-1-benzyl-3,4-bis(tert-butoxycarbonyl-aminomethyl)pyrrolidine thusobtained in methanol (5 ml) were added 50 mg of 10% palladium on carbonand 0.25 ml (6.6 mmol) of formic acid, and the mixture was stirred for 4hours at room temperature. The catalyst was removed from the reactionmixture by suction filtration through Celite, and the filtrate wasconcentrated under reduced pressure. The resultant crude oil waspurified by column chromatography on silica gel, thereby obtaining 165mg (quantitative) oftrans-3,4-bis(tert-butoxycarbonylaminomethyl)pyrrolidine as a colorlessoil.

[0389] To a solution of 145 mg (0.44 mmol) oftrans-3,4-bis(tert-butoxycarbonylaminomethyl)pyrrolidine synthesized bythe process described above in acetonitrile (1.5 ml) were added 0.20 ml(2.7 mmol) of a 37% aqueous solution of formaldehyde and 46.9 mg (0.75mmol) of sodium cyanoboro-hydride. The mixture was stirred for 20minutes at room temperature. Acetic acid was then added to the resultantsolution to adjust its pH to about 5. The solution was stirred for anadditional 30 minutes at room temperature. A 1N aqueous solution ofsodium hydroxide was added to the reaction mixture to adjust the pH ofthe reaction mixture to about 10, and extraction was then conducted withchloroform. An organic layer was dried over anhydrous sodium sulfate andthen concentrated under reduced pressure. The resultant crude oil waspurified by column chromatography on silica gel to obtain 90.1 mg(yield: 60%) of crude crystals of the title compound.

Example 44

[0390] Preparation oftrans-1-methyl-3,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoylaminomethyl]-pyrrolidine:

[0391] A solution of 81 mg (0.24 mmol) oftrans-1-methyl-3,4-bis(tert-butoxycarbonylaminomethyl)pyrrolidinesynthesized by the process described in Referential Example 2 inmethylene chloride (1 ml) was cooled in an ice bath. To the solution wasadded trifluoroacetic acid (0.5 ml), and the mixture was stirred for 2hours. The reaction mixture was concentrated under reduced pressure toobtain an oil containing trans-1-methyl-3,4-bis(aminomethyl)-pyrrolidinetritrifluoroacetate. In accordance with the same process as in Example4, 97 mg (yield: 64%) of crude crystals of the title compound wereobtained from this oil and 153 mg (0.58 mmol) of5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoic acid. The crude crystalswere recrystallized from chloroform-diethyl ether, thereby obtaining acolorless crystalline powder. Melting point: 197-200° C. ¹H-NMR(DMSO-d₆, 120° C.) δ:

[0392] 1.97-2.12(m,2H), 2.25(s,3H), 2.30(dd,J=9.2,5.0 Hz,2H),

[0393] 2.64(dd,J=9.2,6.4 Hz,2H), 3.12-3.29(m,4H), 3.72(s,6H),

[0394] 3.80(s,12H), 6.12(d,J=15.1 Hz,2H), 6.78(d,J=15.6 Hz,2H),

[0395] 6.79(s,4H), 6.87(dd,J=15.6,9.6 Hz,2H),

[0396] 7.16(dd,J=15.1,9.6 Hz,2H), 7.59(br t,J=5.4 Hz,2H).

Referential Example 3

[0397] Preparation oftrans-3,4-bis(tert-butoxycarbonyl-amino)-1-methylpyrrolidine:

[0398] Added to a solution of 770 mg (2.5 mmol) oftrans-3,4-bis(tert-butoxycarbonylamino)pyrrolidine⁽¹⁾ in acetonitrile(11 ml) were 1.1 ml (15 mmol) of a 37% aqueous solution of formaldehydeand 270 mg (4.3 mmol) of sodium cyanoborohydride. The mixture wasstirred for 20 minutes at room temperature. Acetic acid was then addedto the resultant solution to adjust its pH to about 5. The solution wasstirred for an additional 30 minutes at room temperature. A 2.5N aqueoussolution of sodium hydroxide was added to the reaction mixture to adjustthe pH of the reaction mixture to about 10, and extraction was thenconducted with chloroform. An organic layer was dried over anhydroussodium sulfate and then concentrated under reduced pressure. Theresultant crude oil was purified by column chromatography on silica gelto obtain 730 mg (yield: 91%) of the title compound as a colorless oil.(1) Yoon, S.; Still, W. C., Tetrahedron, 1995, 51, 567-578.

Example 45

[0399] Preparation oftrans-3,4-bis[5-(3,4,5-trimethoxy-phenyl)penta-(2E,4E)-dienoylamino]-1-methylpyrrolidinehydrochloride:

[0400] A 4N ethyl acetate solution (2 ml) of hydrogen chloride was addedto a solution of 100 mg (0.32 mmol) oftrans-3,4-bis(tert-butoxycarbonylamino)-1-methylpyrrolidine synthesizedby the process described in Referential Example 3 in tetrahydrofuran (2ml). The mixture was stirred for 2 hours at room temperature and foradditional 30 minutes at 50° C. The reaction mixture was concentratedunder reduced pressure, thereby obtaining 80 mg of oil containingtrans-3,4-diamino-1-methylpyrrolidine trihydrochloride. In accordancewith the same process as in Example 4, 66 mg (yield: 34%) oftrans-3,4-bis[5-(3,4,5-trimethoxyphenyl)-penta-(2E,4E)-dienoylamino]-1-methyl-pyrrolidinewas obtained as a pale yellow amorphous powder from 80 mg of this oiland 184 mg (0.70 mmol) of5-(3,4,5-trimethoxy-phenyl)penta-(2E,4E)-dienoic acid. To a solution ofthe thus-obtained amorphous powder in ethanol (1 ml) was added 0.10 ml(0.10 mmol) of 1N hydrochloric acid, and the resultant mixture wasconcentrated under reduced pressure, thereby obtaining the titlecompound as a pale yellow amorphous powder. ¹H-NMR (data for free baseof the title compound) (DMSO-d₆, 120° C.) δ:

[0401] 2.27(s,3H), 2.60-2.70(m,2H), 3.10-3.20(m,2H),

[0402] 3.72(s,6H), 3.82(s,12H), 4.20-4.30(m,2H),

[0403] 6.13(d,J=15.9 Hz,2H), 6.81(s,4H), 6.73-6.92(m,4H),

[0404] 7.16(dd,J=15.0,10.0 Hz,2H), 7.80-7.90(m,2H).

Example 46

[0405] Preparation ofN,N′-bis[3-(3,4,5-trimethoxyphenyl)-2-propynoyl]-1,3-diaminopropane:

[0406] In accordance with the same process as in Example 1, crudecrystals were obtained from 260 mg (1.1 mmol) of3-(3,4,5-trimethoxyphenyl)-2-propynoic acid and 37 mg (0.51 mmol) of1,3-diaminopropane. The crude crystals were recrystallized fromacetone-diethyl ether, thereby obtaining 118 mg (yield: 46%) of thetitle compound as a colorless crystalline powder.

[0407] Melting point: 158-160° C.

[0408]¹H-NMR (CDC1₃) δ:

[0409] 1.78(br tt,J=6.2,6.2 Hz,2H),

[0410] 3.46(br dt,J=6.2,6.2 Hz,4H), 3.85(s,12H), 3.88(s,6H),

[0411] 6.56(br t,J=6.2 Hz,2H), 6.79(s,4H).

Example 47

[0412] Preparation ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-pent-(2E)-ene-4-ynoyl]-1,2-diaminobenzene:

[0413] In accordance with the same process as in Example 4, 92 mg(yield: 77%) of crude crystals of the title compound were obtained from115 mg (0.44 mmol) of 5-(3,4,5-trimethoxyphenyl)pent-(2E)-ene-4-ynoicacid and 22 mg (0.20 mmol) of 1,2-diaminobenzene. The crude crystalswere recrystallized from ethyl acetate-hexane, thereby obtaining a paleyellow needles.

[0414] Melting point: 232-234° C.

[0415]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0416] 3.74(s,6H), 3.80(s,12H), 6.70(d,J=15.6 Hz,2H),

[0417] 6.87(d,J=15.6 Hz,2H), 7.15-7.21(m,2H), 7.64-7.71(m,2H),

[0418] 9.33(br s,2H).

Example 48

[0419] Preparation oftrans-N,N′-bis[3-(3,4-dihydro-6,7,8-trimethoxy-2-naphthyl)prop-(2E)-enoyl]-1,2-diaminocyclohexane:

[0420] In accordance with the same process as in Example 4, 165 mg(yield: 99%) of crude crystals of the title compound were obtained from160 mg (0.55 mmol) of3-(3,4-dihydro-6,7,8-trimethoxy-2-naphthyl)prop-(2E)-enoic acid and 29mg (0.25 mmol) of trans-1,2-diaminocyclohexane. The crude crystals wererecrystallized from chloroform-hexane, thereby obtaining a pale yellowcrystalline powder. Melting point: 189-191° C. ¹H-NMR (DMSO-d₆, 120° C.)δ:

[0421] 1.23-1.38(m,4H), 1.60-1.75(m,2H), 1.90-2.00(m,2H),

[0422] 2.36(dd,J=8.0,8.0 Hz,4H), 2.74(dd,J=8.0,8.0 Hz,4H),

[0423] 3.40-3.55(m,2H), 3.73(s,6H), 3.78(s,6H), 3.81(s,6H),

[0424] 6.04(d,J=15.4 Hz,2H), 6.60(s,2H), 6.83(s,2H),

[0425] 7.18(d,J=15.4 Hz,2H), 7.35-7.42(m,2H).

Example 49

[0426] Preparation of1,4-bis[3-(6,7,8-trimethoxy-2-naphthyl)prop-(2E)-enoylaminomethyl]cyclohexane:

[0427] In accordance with the same process as in Example 4, 40 mg(yield: 60%) of the title compound was obtained as a pale yellowamorphous powder from 60 mg (0.21 mmol) of3-(6,7,8-trimethoxy-2-naphthyl)prop-(2E)-enoic acid and 14 mg (0.10mmol) of 1,4-bis(aminomethyl)cyclohexane. ¹H-NMR (DMSO-d₆, 120° C.)(mixture of diastereomers; mixture of amide rotamers; no amide C(O)NHproton was observed) δ:

[0428] 1.43-1.55(m,8H), 1.75-1.85(m,2H), 3.09(m,1H),

[0429] 3.20(m,1H), 3.45-3.53(m,2H), 3.88(s,6H), 3.93(s,6H),

[0430] 4.00(s,6H), 6.69(d,J=15.6 Hz,2H), 7.50-7.56(m,2H),

[0431] 7.57-7.65(m,2H), 7.12(s,2H), 7.74(d,J=8.5 Hz,2H),

[0432] 8.04(s,2H).

Example 50

[0433] Preparation ofN,N-bis[N-[3-(5,6-dimethoxy-1,1-dimethyl-2-indenyl)prop-(2E)-enoyl]-3-aminopropyl]-methylamine:

[0434] In accordance with the same process as in Example 1, 30 mg(yield: 95%) of the title compound was obtained as a pale yellowamorphous powder from 30 mg (0.11 mmol) of3-(5,6-dimethoxy-1,1-dimethyl-2-indenyl)prop-(2E)-enoic acid and 7.0 mg(0.048 mmol) of N,N-bis(3-aminopropyl)methylamine. ¹H-NMR (DMSO-d6, 120°C.) δ:

[0435] 1.31(s,12H), 1.50-1.68(m,4H), 2.19(s,3H),

[0436] 2.38(t,J=7.0 Hz,4H), 3.15-3.25(m,4H), 3.76(s,6H),

[0437] 3.81(s,6H), 6.30(d,J=16.1 Hz,2H), 6.89(s,2H),

[0438] 6.98(s,2H) 7.04(s,2H), 7.25(d,J=16.1 Hz,2H),

[0439] 7.58-7.67(m,2H).

Example 51

[0440] Preparation ofN,N′-bis[4-(3,4,5-trimethoxyphenyl)-benzoyl]-3,4-diaminopyridine:

[0441] In accordance with the same process as in Example 4, 100 mg(yield: 77%) of crude crystals of the title compound were obtained from230 mg (0.80 mmol) of 4-(3,4,5-trimethoxyphenyl)benzoic acid and 22 mg(0.20 mmol) of 3,4-diaminopyridine. The crude crystals wererecrystallized from ethanol-hexane, thereby obtaining pale yellowneedles.

[0442] Melting point: 225-226° C.

[0443]¹H-NMR (mixture of amide rotamers) (DMSO-d₆, 120° C.) δ:

[0444] 3.75(s,3H), 3.76(s,3H), 3.86(s,6H), 3.87(s,6H),

[0445] 6.96(s,2H), 6.97(s,2H), 7.74-7.82(m,4H),

[0446] 7.97(br d,J=5.3 Hz,1H), 7.99(d,J=8.7 Hz,2H),

[0447] 8.06(d,J=8.7 Hz,2H), 8.41(d,J=5.3 Hz,1H), 8.75(br s,1H),

[0448] 9.96(br s,2H).

Example 52

[0449] Preparation ofN,N′-bis[5-nitro-2-(3,4,5-trimethoxy-phenyl)benzoyl]ethylenediamine:

[0450] In accordance with the same process as in Example 1, 61 mg(yield: 88%) of crude crystals of the title compound were obtained from73 mg (0.22 mmol) of 5-nitro-2-(3,4,5-trimethoxyphenyl)benzoic acid and6.0 mg (0.10 mmol) of ethylenediamine. The crude crystals wererecrystallized from methylene chloride-hexane, thereby obtaining a paleyellow crystalline powder.

[0451] Melting point: at least 250° C.

[0452]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0453] 3.13-3.21(m,4H), 3.74(s,6H), 3.78(s,12H), 6.74(s,4H),

[0454] 7.68(d,J=8.5 Hz,2H), 7.93-8.01(m,2H),

[0455] 8.18(d,J=2.4 Hz,2H), 8.23(dd,J=8.5,2.4 Hz,2H).

Example 53

[0456] Preparation ofN,N′-bis[5-amino-2-(3,4,5-trimethoxy-phenyl)benzoyl]ethylenediamine:

[0457] To a solution of 20 mg (0.028 mmol) ofN,N′-bis[5-nitro-2-(3,4,5-trimethoxy-phenyl)benzoyl]ethylenediaminesynthesized by the process of Example 52 in acetic acid-ethyl acetate(1:3, 2 ml) was added 20 mg of 10% palladium on carbon, and the mixturewas stirred for 3 hours at room temperature under hydrogen. The catalystwas removed from the reaction mixture by suction filtration throughCelite, and the filtrate was concentrated under reduced pressure. Asolution of the resultant residue in chloroform was washed with asaturated solution of a sodium hydrogencarbonate and a saturated salinesolution, dried over anhydrous sodium sulfate, and then concentratedunder reduced pressure, thereby obtaining 17 mg (quantitative) of crudecrystals of the title compound. The crude crystals were recrystallizedfrom methylene chloride-diethyl ether, thereby obtaining a pale yellowcrystalline powder. Melting point: at least 250° C. ¹H-NMR (DMSO-d₆,120° C.) δ:

[0458] 2.98-3.15(m,4H), 3.69(s,6H), 3.74(s,12H),

[0459] 4.86(br s,4H), 6.56(s,4H), 6.61(d,J=2.4 Hz,2H),

[0460] 6.65(dd,J=8.2,2.4 Hz,2H), 7.04(d,J=8.2 Hz,2H),

[0461] 7.25-7.33(m,2H).

Example 54

[0462] Preparation ofN,N′-bis[5-(3,4,5-trimethoxyphenyl)-3-pyridinecarbonyl]-N,N′-dimethyl-1,6-diaminohexane:

[0463] In accordance with the same process as in Example 1, 101 mg(yield: 97%) of the title compound was obtained as a pale yellowamorphous powder from 95 mg (0.33 mmol) of5-(3,4,5-trimethoxyphenyl)-3-pyridinecarboxylic acid and 22 mg (0.15mmol) of N,N′-dimethyl-1,6-diaminohexane. ¹H-NMR (DMSO-d₆, 120° C.) δ:

[0464] 1.22(t,J=6.8 Hz,4H), 1.49-1.64(m,4H), 2.91(s,6H),

[0465] 3.23-3.40(m,4H), 3.75(s,6H), 3.83(s,12H), 6.96(s,4H),

[0466] 7.97(dd,J=2.1,1.9 Hz,2H), 8.48(d,J=1.9 Hz,2H),

[0467] 8.88(d,J=2.1 Hz,2H).

Example 55

[0468] Preparation of1,4-bis[4-fluoro-3-(3,4,5-trimethoxy-phenyl)benzoylaminomethyl]benzene:

[0469] In accordance with the same process as in Example 1, 130 mg(yield: 91%) of the title compound was obtained as a colorless amorphouspowder from 135 mg (0.44 mmol) of4-fluoro-3-(3,4,5-trimethoxyphenyl)benzoic acid and 27 mg (0.20 mmol) of1,4-bis(aminomethyl)benzene. ¹H-NMR (mixture of amide rotamers)(DMSO-d₆, 120° C.) δ:

[0470] 3.76(s,6H), 3.82(s,12H), 4.47(d,J=5.9 Hz,4H),

[0471] 6.82(s,2H), 6.83(s,2H), 7.28(dd,J=10.4,8.5 Hz,2H),

[0472] 7.29(s,4H), 7.87(ddd,J=8.5,4.8,2.4 Hz,2H),

[0473] 7.98(dd,J=7.5,2.4 Hz,2H), 8.63(br t,J=5.9 Hz,2H).

Example 56

[0474] Preparation ofN,N′-bis[4-methyl-3-(3,4,5-trimethoxy-phenyl)benzoyl]ethylenediamine:

[0475] In accordance with the same process as in Example 1, 100 mg(yield: 79%) of crude crystals of the title compound were obtained from133 mg (0.44 mmol) of 4-methyl-3-(3,4,5-trimethoxyphenyl)benzoic acidand 12 mg (0.20 mmol) of ethylenediamine. The crude crystals wererecrystallized from ethanol-hexane, thereby obtaining a colorlesscrystalline powder.

[0476] Melting point: 204-206° C.

[0477]¹H-NMR (mixture of amide rotamers) (DMSO-d₆, 120° C.) δ:

[0478] 2.27(s,6H), 3.47-3.49(m,4H), 3.75(s,6H), 3.79(s,12H),

[0479] 6.57(s,4H), 7.30(d,J=7.8 Hz,2H), 7.68(br d,J=1.9 Hz,2H),

[0480] 7.69(br dd,J=7.8,1.9 Hz,2H), 8.07-8.17(m,2H).

Example 57

[0481] Preparation ofN,N′-bis[4-methoxy-3-(3,4,5-trimethoxyphenyl)benzoyl]-1,4-diaminobenzene:

[0482] In accordance with the same process as in Example 4, crudecrystals were obtained from 98 mg (0.31 mmol) of4-methoxy-3-(3,4,5-trimethoxyphenyl)benzoic acid and 25 mg (0.14 mmol)of 1,4-diaminobenzene dihydrochloride. The crude crystals wererecrystallized from methanol-chloroform-diethyl ether, thereby obtaining52 mg (yield: 53%) of the title compound as a pale yellow crystallinepowder.

[0483] Melting point: at least 250° C.

[0484]¹H-NMR (DMSO-d₆, 120° C.) δ:

[0485] 3.77(s,6H), 3.83(s,12H), 3.86(s,6H), 6.83(s,4H),

[0486] 7.19(d,J=8.5 Hz,2H), 7.69(s,4H), 7.94(d,J=2.0 Hz,2H),

[0487] 7.96(dd,J=8.5,2.0 Hz,2H), 9.73(s,2H).

Test Example 1

[0488] Evaluation of inhibitory effect on production of IgE antibody:

[0489] A spleen was enucleated from a mouse (Balb/C, male, aged 8 weeks)and shredded in 0.3% BSA/HBSS to prepare single cells by means of a200-mesh screen. Further, the single cells were hemolyzed by 0.75%ammonium chloride-17 mM Tris solution to prepare a splenocyte suspension(1×10⁷/ml) using RPMI 1640 medium/25 mM HEPES/0.3% BSA. After thesuspension was reacted with a mouse anti-mouse Thy-1.2 monoclonalantibody (product of Cedarlane Co.) at 4° C. for 1 hour, the reactionmixture was centrifuged, and the sediment cells were suspended again(1×10⁷/ml, RPMI/HEPES/BSA). After the suspension was then reacted with alow-cytotoxic rabbit complement (product of Cedarlane Co.) at 37° C. for1 hour, killed cells were removed by specific gravity centrifugationusing lympholyte M (product of Cedarlane Co.) to obtain a B cellfraction as viable cells.

[0490] After B cells (10⁵/0.2 ml/well) were cultured for a day togetherwith LPS (i E. coli 026:B6, product of DIFCO Co.) using a 96-well plate,mouse IL-4 (product of Genzyme Co.) was added to conduct culture furtherfor 7 days.

[0491] Each test was added on the first day of the culture, and theamount of IgE in a culture supernatant was meausred by ELISA after theculture, thereby calculating out the inhibitory effect of the agent onthe production of an IgE antibody. The inhibitory activities of the testagents at a concentration of 10-5 M are shown in Table 1. TABLE 1Inhibitory effect on Test compound (Example No.) production of IgE (%) 5 90 15 100  22 90 26 85 38 80

INDUSTRIAL APPLICABILITY

[0492] The diamide compounds (1) according to the present invention havean inhibitory effect on the production of an IgE antibody and are henceuseful as agents for preventing and treating various allergicimmunological diseases in which IgE participates, such as asthma.

1. A compound represented by the following general formula (1):

wherein A is a phenyl, naphthyl, dihydronaphthyl, indenyl, pyridyl,indolyl, isoindolyl, quinolyl or isoquinolyl group which may besubstituted; X is a lower alkylene group which may be substituted; adivalent residue of an alicyclic compound which may be substituted, anaromatic compound which may be substituted, or a heterocyclic compoundwhich may be substituted; an imino group which may be substituted; or asulfur atom or an oxygen atom; Y is a single bond or a lower alkylenegroup; Z is a group of —CH═CH-, —C—C—, —(CH═CH)₂-, —C≡C—CH═CH— or—CH═CH—C≡C—, or a divalent residue of benzene, pyridine, pyrimidine orpyrazine which may be substituted; and R is a hydrogen atom, or a loweralkyl, cycloalkyl, aryl or aralkyl group, with the proviso that A is nota phenyl group, a 4-chlorophenyl group nor a 4-methoxyphenyl group whenX is an ethylene group, Y is a single bond, Z is —C═C—, and R is ahydrogen atom; A is not a 3,4-dichlorophenyl group when X is atrimethylene group, Y is a single bond, Z is —(CH═CH)₂-, and R is ahydrogen atom; and A is not a 3,4-dihydroxyphenyl group, a3-hydroxy-4-methoxyphenyl group, a 3-methoxy-4-hydroxyphenyl group nor a3,4-dimethoxyphenyl group when X is a tetramethylene group, Y is asingle bond, Z is —CH═CH— or —(CH═CH)₂-, and R is a hydrogen atom, asalt thereof, or a solvate thereof.
 2. The compound, the salt thereof,or the solvate thereof according to claim 1 , wherein A is a phenyl,naphthyl, dihydronaphthyl, indenyl, pyridyl, indolyl, isoindolyl,quinolyl or isoquinolyl group which may have 1-3 substituents selectedfrom among a hydroxyl group, halogen atoms, lower alkyl groups which maybe substituted by 1-3 halogen atoms, lower alkoxy groups, an amino groupwhich may be substituted by one or two lower alkyl groups, and loweralkylthio groups.
 3. The compound, the salt thereof, or the solvatethereof according to claim 1 , wherein X is an lower alkylene groupwhich may be substituted by a carboxyl or lower alkoxycarbonyl group. 4.The compound, the salt thereof, or the solvate thereof according toclaim 1 , wherein X is a divalent residue of a cycloalkane having 5-8carbon atoms, which may be substituted by a halogen atom, a hydroxylgroup, a lower alkyl group which may be substituted by a primary,secondary or tertiary amino group, a lower alkoxy group, a carboxylgroup, a lower alkoxycarbonyl group, an amino group, an alkylaminogroup, a dialkylamino group, a nitro group, a cyano group, or an aralkylgroup.
 5. The compound, the salt thereof, or the solvate thereofaccording to claim 1 , wherein X is a phenylene group which may besubstituted by a halogen atom, a hydroxyl group, a lower alkyl groupwhich may be substituted by a primary, secondary or tertiary aminogroup, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonylgroup, an amino group, an alkylamino group, a dialkylamino group, anitro group, a cyano group, or an aralkyl group.
 6. The compound, thesalt thereof, or the solvate thereof according to claim 1 , wherein X isa divalent residue of pyridine, pyrrolidine, piperidine, piperazine orhomopiperazine which may be substituted by a halogen atom, a hydroxylgroup, a lower alkyl group which may be substituted by a primary,secondary or tertiary amino group, a lower alkoxy group, a carboxylgroup, a lower alkoxycarbonyl group, an amino group, an alkylaminogroup, a dialkylamino group, a nitro group, a cyano group, or an aralkylgroup.
 7. A medicine comprising the compound, the salt thereof, or thesolvate thereof according to any one of claims 1 to 6 as an activeingredient.
 8. The medicine according to claim 7 , which is an agent forinhibiting the production of an IgE antibody.
 9. The medicine accordingto claim 7 or 8 , which is an agent for preventing and treating anallergic immunological disease.
 10. The medicine according to any one ofclaims 7 to 9 , which is an agent for preventing and treating asthma,atopic dermatitis, allergic rhinitis, inflammatory large bowel diseaseor contact dermatitis.
 11. A medicinal composition comprising thecompound according to any one of claims 1 to 6 and a pharmaceuticallyacceptable carrier.
 12. Use of the compound according to any one ofclaims 1 to 6 for a medicine.
 13. The use according to claim 12 ,wherein the medicine is an agent for inhibiting the production of an IgEantibody.
 14. The use according to claim 12 , wherein the medicine is anagent for preventing and treating an allergic immunological disease. 15.The use according to claim 12 , wherein the medicine is an agent forpreventing and treating asthma, atopic dermatitis, allergic rhinitis,inflammatory large bowel disease or contact dermatitis.
 16. A method oftreating an allergic immunological disease, which comprisesadministering an effective amount of the compound according to any oneof claims 1 to 6 .
 17. The method according to claim 16 , wherein theallergic immunological disease is asthma, allergic rhinitis,inflammatory large bowel disease or contact dermatitis.